BRET and Schizophrenia

Research Question: To what extent do the D3 and D4 receptors play a role in mediating a response to a schizophrenia drug? What implications would this have for the need for more highly specific drugs in the future?

Metabotropic (7-TM GPCRs) receptors are a major family of membrane receptors (the largest, most diverse group in eukaryotes comprising the largest class in the human genome). GPCRs are also the target for ~50% of drugs on the market, and yet only a small portion of GPCRs have been tested, leaving the possibility for great potential in the field of receptor pharmacology. All 5 dopamine receptors are metabotropic, with the D2/D3/D4 receptors exhibiting close homology and the D1/D5 receptors exhibiting a close homology. While the D2 receptor is often implicated in contributing to reward in the human midbrain, the question of the effects of drugs on the D3 and D4 receptor suddenly becomes relevant. Many of the dopaminergic pathways originate in the midbrain (like the substantia nigra) and one of the hallmarks of schizophrenia is dysregulated doapminergic pathways (like excess dopamine in the midbrain). Traditional antipsychotics are antagonists of the D2 receptor which can alleviate the symptoms associated with the midbrain, but not with the forebrain where the dopamine is already depleted.

Using BRET assay, it is my hope that I will be successful in seeing how a new schizophrenia drug may act on the Dopamine 3 and 4 receptors which previously have been essentially disregarded. Due to recent publications commenting on the widespread distribution of the D3 and D4 receptors in the cortex, it is now important to not only observe the effects of biased signaling but also of signaling associated with receptor specificity.

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